Gray zone and the need for expansion in chronic hepatitis B: From theory to clinical practice

Table 2 Conventional international guideline approaches to grey zone hepatitis B: Recommendations and limitations

Guideline	Recommendation for GZ	Limitations
Asian Pacific Association for the Study of the Liver (2016, updated 2021)	Therapy if HBV DNA > 2000 IU/mL and histological evidence of damage; normal ALT often delays treatment	Requires invasive biopsy; limited access to advanced diagnostics in low-resource settings; no clear GZ protocol
American Association for the Study of Liver Diseases (2018)	Antiviral therapy if HBV DNA > 2000 IU/mL, ALT > 2 × upper limit of normal, or fibrosis ≥ F2. GZ patients often excluded unless biopsy-confirmed damage	Heavy reliance on ALT thresholds; no specific GZ criteria; limited guidance for normal ALT with high HBV DNA
European Association for the Study of the Liver (2017, updated 2022)	Therapy considered for HBV DNA > 2000 IU/mL, age > 30, or family history of hepatocellular carcinoma, even with normal ALT	Inconsistent ALT thresholds; lack of GZ-specific trial data; variable adoption across regions

ALT: Alanine aminotransferase; GZ: Grey zone; HBV: Hepatitis B virus.